Genetic Variant SAXO1:p.Ser458Pro (chr9-18928105-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_153707.4(SAXO1):c.1372T>C(p.Ser458Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S458C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SAXO1
NM_153707.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.74

Publications

0 publications found

Variant links:

Genes affected

SAXO1 (HGNC:28566): (stabilizer of axonemal microtubules 1) Enables microtubule binding activity. Involved in several processes, including cold acclimation; positive regulation of cilium assembly; and protein stabilization. Located in microtubule cytoskeleton and sperm flagellum. [provided by Alliance of Genome Resources, Apr 2022]

SAXO1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12134403).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAXO1	NM_153707.4 link	c.1372T>C	p.Ser458Pro	missense_variant	Exon 4 of 4	ENST00000380534.9	NP_714918.2	Q8IYX7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SAXO1	ENST00000380534.9 link	c.1372T>C	p.Ser458Pro	missense_variant	Exon 4 of 4	1	NM_153707.4	ENSP00000369907.4	Q8IYX7
SAXO1	ENST00000542071.2 link	c.1177T>C	p.Ser393Pro	missense_variant	Exon 4 of 4	3		ENSP00000438823.2	F6S232
SAXO1	ENST00000649457.1 link	c.1177T>C	p.Ser393Pro	missense_variant	Exon 4 of 12			ENSP00000497677.1	F6S232
SAXO1	ENST00000380530.1 link	c.*947T>C		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000369902.1	Q5VZT6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461438

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726928

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111674

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 08, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1372T>C (p.S458P) alteration is located in exon 4 (coding exon 4) of the SAXO1 gene. This alteration results from a T to C substitution at nucleotide position 1372, causing the serine (S) at amino acid position 458 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.018

.;T;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.60

.;T;T

M_CAP

Benign

0.0044

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

1.7

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.67

.;N;.

REVEL

Benign

0.19

Sift

Uncertain

0.029

.;D;.

Sift4G

Uncertain

0.027

.;D;D

Polyphen

0.016

.;B;.

Vest4

0.19, 0.21

MutPred

0.10

.;Loss of phosphorylation at S458 (P = 0.0255);.;

MVP

0.15

MPC

0.0039

ClinPred

0.15

GERP RS

4.9

Varity_R

0.20

gMVP

0.29

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over